Project Summary/Abstract: This is a GO application to ddress "Mechanisms of Alcohol and Nicotine Co-Dependence" as the area of scientific priority. The GO mechanism is used because this application requires a multi-lab approach to accelerate current and future research. The objective of this proposal is to provide a better understanding of the mechanisms underlying the interactions of the reinforcing effects of ethanol (EtOH) and nicotine (NIC) in promoting co-abuse. The overall hypothesis to be tested is that administration of EtOH or NIC will produce cross-sensitization to the reinforcing effects of the other, which promotes the potential for their co-abuse. The ventral tegmental area (VTA) is a site supporting the reinforcing actions of EtOH and NIC, and is an excellent starting point for studying the interactions of EtOH and NIC. Since genetic factors contribute to the abuse potential of drinking and smoking, an animal model that has demonstrated both EtOH and NIC abuse independently will be used, i.e., the selectively bred alcohol-preferring (P) rat. Operant techniques will be used for the intra-cranial self-administration and i.v. NIC self-administration experiments. Microdialysis-HPLC procedures will be used to measure extracellular levels of dopamine (DA) and glutamate. Targeted gene expression changes will be measured with quantitative RT-PCR. The aims are designed to determine the effects of EtOH and NIC administration on the sensitivity of the mesolimbic system to the reinforcing effects of the other drug, if these reinforcing effects are associated with increased response of DA neurons to the drug, and whether EtOH and NIC interact synergistically. Another aim is designed to establish an animal model of co-abuse of EtOH and NIC, and to determine the effects of co-abuse of EtOH and NIC on the expression of genes for addiction-associated receptors or receptor subunits for DA, GABA, glutamate, 5-HT and nicotinic systems. Another aim is designed to identify changes in the activity of DA and glutamatergic neuronal pathways within the mesolimbic system that are associated with EtOH and NIC co-abuse. Overall, the results of this project will provide a better understanding of the neurobiological basis for the interactions of EtOH and NIC that contribute to their co-abuse. This is an important initial step toward developing treatment strategies to reduce their use and co-abuse. Since alcohol drinking and smoking affect millions of people, this project has potential far reaching impact on improving the health and lives of many individuals. PUBLIC HEALTH RELEVANCE: The co-use of alcohol and tobacco is common and affects millions of people. When used together, alcohol and tobacco compound the health risks found with their individual use. The long-range goals of this project are to better understand the brain mechanisms underlying the co-abuse of alcohol and nicotine, so that treatment strategies can be developed to reduce or prevent their use.